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Proteasomal degradation of polycomb-group protein CBX6 confers MMP-2 expression essential for mesothelioma invasion

Katsuya Sakai1,2, Takumi Nishiuchi3, Shoichiro Tange4

  • 1Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kanazawa, 920-1192, Japan. k_sakai@staff.kanazawa-u.ac.jp.

Scientific Reports
|October 8, 2020
PubMed

Insights

Chromobox 6 (CBX6) instability promotes malignant mesothelioma invasion by increasing matrix metalloproteinase-2 (MMP-2) expression. Loss of nuclear CBX6 in malignant mesothelioma suggests its proteasomal degradation drives cancer progression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Malignant mesothelioma's aggressive invasiveness poses challenges for cancer therapy.
  • The molecular mechanisms driving mesothelioma invasiveness are not fully understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying malignant mesothelioma invasiveness.
  • To investigate the role of Polycomb Repressive Complex (PRC) components in mesothelioma progression.

Main Methods:

  • Correlation analysis of matrix metalloproteinase-2 (MMP-2) gene expression with invasive phenotype.
  • Investigating MMP-2 regulation by DNA and histone methylation.
  • Chromobox 6 (CBX6) knockdown and transcriptome analysis.
  • Assessment of CBX6 protein stability via ubiquitination and degradation assays.
  • Immunohistochemical analysis of CBX6 expression in human tissues.

Main Results:

  • MMP-2 expression is crucial for mesothelioma cell invasion and correlates with invasiveness.
  • MMP-2 gene expression is epigenetically regulated by methylation, involving PRC.
  • CBX6 knockdown enhances MMP-2 expression and mesothelioma cell invasion.
  • CBX6 regulates genes associated with cancer cell migration and metastasis.
  • CBX6 is unstable in invasive cells due to proteasomal degradation and is lost in malignant mesothelioma tissues.

Conclusions:

  • Epigenetic regulation of MMP-2 by CBX6 is a key mechanism in mesothelioma invasiveness.
  • Proteasomal degradation of CBX6 contributes to mesothelioma progression.
  • CBX6 loss is a potential biomarker for malignant mesothelioma.

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